The long range goal of this research is to understand the molecular mechanisms regulating cortical synaptogenesis in normal aging and in degenerative brain disorders. During both normal aging and in developing Alzheimer's disease this neuronal death is accompanied by a dramatic reduction in synaptic density. However, in normal aging synaptic density is maintained, suggesting that surviving neurons sprout to maintain synaptic density. Although the factors responsible for initiating and promoting synaptic sprouting in the brain are poorly defined, members of the neuregulin (NRG) family of growth and differentiation factors are likely candidates as these molecules have potent direct and indirect effects on multiple aspects of neuronal differentiation, including induction of neurite outgrowth and modulation of the expression of multiple channels and neurotransmitter receptors. Based on our preliminary observations, we hypothesize that NRGs critically regulate reactive synaptogenesis either by acting directly on neuronal erbB receptors or acting indirectly through associated glia. To test our hypothesis, we propose an integrated approach in which NRG and erbB expression will be examined in human brain tissue from Alzheimer's disease patients and normal aged controls and these observations compared to a well-characterized animal model of reactive synaptogenesis. We will test the hypothesis that: 1) NRGs and their erbB receptors continue to be expressed in hippocampus and neocortex from normal aging humans, but this expression is altered in hippocampus and neocortex from Alzheimer's disease patients; 2) NRGs and erbB2-4 receptors are up-regulated during reactive synaptogenesis in injured rat brain; and 3) blockade of NRG action with a neutralizing erbB4-IgG fusion protein decreases the ability of crossed entorhinal and commissural projections to sprout collaterals in the dentate molecular layer following a lesions of the ipsilateral entorhinal cortex. The proposed research plan represents a natural progression of our work to date and will provide useful insights into the molecular mechanisms regulating the induction of synaptic sprouting in Alzheimer's disease patients and normal aging humans.